This is a competing renewal application of the Program Project Grant entitled INTEGRATIVE CONSEQUENCES OF HYPOXIA. The overall focus of the Program continues to examine the effects of systemic, cellular and molecular responses to chronic intermittent hypoxia (CIH). The overarching hypotheses of the competing renewal application are: a) ROS affect chemo reflex function by recruiting distinct cellular mechanisms in the individual components of the chemo reflex pathway (sensor, controller, and end organ); and b) Long-term exposure to CIH leads to stable changes in ROS as well as cardio respiratory functions and involves epigenetic regulation of redox homeostasis in the chemo reflex pathway. PROJECT 1 will test the hypothesis that the effects of CIH on the carotid body are due to ROS-mediated imbalance between inhibitory (carbon monoxide; CO) and excitatory (hydrogen sulfide; H2S) gaseous messengers. PROJECT 2 tests the hypothesis that chemo reflex triggered sympathetic activation by CIH evokes oxidative stress in the adrenal medulla, a major sympathetic end organ resulting in augmented catecholamine secretion by hypoxia, which contributes to ClH-induced hypertension. PROJECT 3 tests the hypothesis that the ClH-induced irregular breathing is mediated by carotid body-dependent ROS generation and reconfiguration of the respiratory neural network in the PreBotC. PROJECT 4 tests the hypothesis that epigenetic regulation of genes encoding redox regulatory enzymes in the chemo reflex pathway contributes to persistent oxidative stress, and the cardio-respiratory responses to long-term CIH. CORE A fulfills an administrative and coordinating function. CORE B provides centralized facilities for exposure of rodents to CIH, maintenance of genetically modified mice, morphological, biochemical and molecular biological assays for all four projects. Because of the tight thematic linkages across the projects, the total knowledge gained from the overall program will truly be greater than the sum derived from each project.